Patent GB-830519-A (GB)
Title: Improvements in or relating to diquaternary compounds
Inventor: COKER GEOFFREY GEORGE
IPC: C07D333/20
Filed: 1956-03-15
Abstract: The invention comprises compounds of the general formula <FORM:0830519/IV (b)/1> (wherein R1 is a phenyl or 2-thienyl group, R2 i a 2-pyridyl or 2-thienyl group, X is C : CH or CH.CH2, m is an integer from 1 to 5, n is 2 or 3, \sNN1 is a quaternary nitrogen atom carrying two alkyl groups together having up to 5 carbon atoms, \sNN2 is a quaternary nitrogen atom carrying at least one alkyl group of 1-4 carbon atoms and either carrying two further alkyl groups giving a total of up to 9 carbon atoms or forming part of a pyrolidine, piperidine or morpholine ring, and A- is an anion of an inorganic or organic acid), and the preparation thereof by the action of a quaternizing agent, such as an alkyl halide or dialkyl sulphate, chosen to give the desired substitution at \sNN1 and \sNN2, on a ditertiary amine of the general formula <FORM:0830519/IV (b)/2> (wherein N3 and N4 are tertiary nitrogen atoms). Examples describe the preparation of diquaternary iodides, in which the iodide ion may be subsequently replaced by other anions; e.g. treatment with silver chloride gives chlorides, whilst contact with a suitable ion-exchange resin gives hydroxides from which any desired salt may be prepared. The Provisional Specification comprises also compounds in which X is C(OH).CH2.  The products are useful as ganglion blocking agents. Ditertiary amines of the second general formula above are prepared as follows: when R1 and R2 are the same, a lower alkyl ester of an acid of the general formula <FORM:0830519/IV (b)/3> is reacted with an organolithium compound R1Li: when R1 and R2 are different, a ketone of the general formula <FORM:0830519/IV (b)/4> is reacted with the organolithium compound R2Li.  These reactions give the ditertiary amines in which X is C(OH).CH2, which are then dehydrated to those in which X is C : CH, and the latter, if desired, reduced to those in which X is CH.CH2.  Acid addition salts of these compounds are described.  (Certain of the foregoing esters and ketones are prepared as described below.)  3-(N - Methyl - N - 2 - piperidinoethylamino)-1-phenylpropan-1-one is prepared (as dihydrochloride) by refluxing acetophenone, paraformaldehyde and N-methyl-N-2-piperidinoethylamine in aqueous ethanolic hydrochloric acid.  6 - (N - Methyl - N - 2 - piperidinoethylamino)-1-phenylhexan-1-one is prepared by refluxing 1 : 5-dibromopentane with phenol in aqueous ethanolic caustic potash to form 1-bromo-5-phenoxypentane, refluxing this with sodium cyanide in aqueous ethanolic solution, reacting the resulting 1-cyano-5-phenoxypentane with phenyl-lithium in ether and hydrolysing the resulting complex to 6-phenoxy-1-phenylhexan-1-one, boiling this with hydrobromic acid to give 6-bromo-1-phenylhexan-1-one, and warming this with N-methyl-N-2-piperidinoethylamine.  Ethyl b  - (N - methyl - N - 2 - piperidinoethylamino)-propionate is prepared by refluxing ethyl acrylate with N-methyl-N-(2-piperidinoethyl)-amine. Ethyl 6 - (N - methyl - N - 2 - piperidinoethylamino)-hexanoate is prepared by warming ethyl 6-bromohexanoate with N-methyl-N-2-piperidinoethylamine.  N - Methyl - N - 3 - morpholinopropylamine is prepared by reacting acrylonitrile with 3-morpholinopropylamine to form N-2-cyanoethyl-N-3-morpholinopropylamine, heating this with formaldehyde and formic acid in water, adding caustic soda and pyrolysing the oil thereby precipitated.